Effective atherosclerotic plaque inflammation inhibition with targeted drug delivery by hyaluronan conjugated atorvastatin nanoparticles

Nanoscale. 2020 May 7;12(17):9541-9556. doi: 10.1039/d0nr00308e.

Abstract

Atherosclerosis is associated with inflammation in the arteries, which is a major cause of heart attacks and strokes. Reducing the extent of local inflammation at atherosclerotic plaques can be an attractive strategy to combat atherosclerosis. While statins can exhibit direct anti-inflammatory activities, the high dose required for such a therapy renders it unrealistic due to their low systemic bioavailabilities and potential side effects. To overcome this, a new hyaluronan (HA)-atorvastatin (ATV) conjugate was designed with the hydrophobic statin ATV forming the core of the nanoparticle (HA-ATV-NP). The HA on the NPs can selectively bind with CD44, a cell surface receptor overexpressed on cells residing in atherosclerotic plaques and known to play important roles in plaque development. HA-ATV-NPs exhibited significantly higher anti-inflammatory effects on macrophages compared to ATV alone in vitro. Furthermore, when administered in an apolipoprotein E (ApoE)-knockout mouse model of atherosclerosis following a 1-week treatment regimen, HA-ATV-NPs markedly decreased inflammation in advanced atherosclerotic plaques, which were monitored through contrast agent aided magnetic resonance imaging. These results suggest CD44 targeting with HA-ATV-NPs is an attractive strategy to reduce harmful inflammation in atherosclerotic plaques.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / administration & dosage*
  • Anti-Inflammatory Agents / chemistry
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Atorvastatin / administration & dosage*
  • Atorvastatin / chemistry
  • Atorvastatin / pharmacology
  • Drug Delivery Systems
  • Hyaluronan Receptors / metabolism
  • Hyaluronic Acid / chemistry*
  • Hyaluronic Acid / metabolism
  • Inflammation
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Mice, Knockout
  • Nanoparticles / administration & dosage*
  • Nanoparticles / chemistry
  • Nanoparticles / metabolism
  • Plaque, Atherosclerotic / drug therapy*
  • Plaque, Atherosclerotic / pathology
  • RAW 264.7 Cells

Substances

  • Anti-Inflammatory Agents
  • Apolipoproteins E
  • Hyaluronan Receptors
  • Hyaluronic Acid
  • Atorvastatin